EP1019039B1 - Gepresste nitroglycerintablette und verfahren zu ihrer herstellung - Google Patents

Gepresste nitroglycerintablette und verfahren zu ihrer herstellung Download PDF

Info

Publication number
EP1019039B1
EP1019039B1 EP98948293A EP98948293A EP1019039B1 EP 1019039 B1 EP1019039 B1 EP 1019039B1 EP 98948293 A EP98948293 A EP 98948293A EP 98948293 A EP98948293 A EP 98948293A EP 1019039 B1 EP1019039 B1 EP 1019039B1
Authority
EP
European Patent Office
Prior art keywords
nitroglycerin
composition
lactose
weight
tablets
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP98948293A
Other languages
English (en)
French (fr)
Other versions
EP1019039A1 (de
Inventor
Roberto L. Capella
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Priority to SI9830076T priority Critical patent/SI1019039T1/xx
Publication of EP1019039A1 publication Critical patent/EP1019039A1/de
Application granted granted Critical
Publication of EP1019039B1 publication Critical patent/EP1019039B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

  • the present invention is directed to a nitroglycerin containing pharmaceutical composition, preferably a direct compressed tablet, stabilized by the presence of glyceryl monostearate.
  • the formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g., adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g., friability and weight variations).
  • the stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored.
  • the preferred combination of components are: nitroglycerin/lactose dilution, hydrous lactose, glyceryl monostearate, fumed silica, pregelatinized starch and calcium stearate.
  • the preferred process employs direct compression technology to yield a stabilized composition showing adequate disintegration and bioavailability.
  • nitroglycerin which is a liquid at normal temperatures, easily migrates from tablets to other tablets and/or to the container and container components. Nitroglycerin will migrate to the cap-liner and to other tablets such as aspirin if the two products are stored together in the same container. Plastics have various affinities for nitroglycerin depending on their polarity; hence tablets have not been successfully marketed in unit dose containers. In fact, the USP states that nitroglycerin tablets must be stored in glass containers.
  • MCC microcrystalline cellulose
  • PVP polyvinylpyrrolidone
  • BCD ⁇ -cyclodextrin
  • MCC microcrystalline cellulose
  • PVP polyvinylpyrrolidone
  • BCD ⁇ -cyclodextrin
  • a compressed tablet was prepared using the combination of MCC and PVP and marketed by Warner Chilcott Laboratories as NitroPRN®. The tablet was far superior to the current molded tablets with respect to nitroglycerin migration and volatility.
  • the high amount of water insoluble excipient (MCC) was not desirable since the tablet gave a less acceptable feel and slower disintegration under the tongue.
  • nitroglycerin sublingual tablets is typically the traditional molded tablet method.
  • a wet mixture of nitroglycerin concentrate and other ingredients is made and, while moist, is pressed into cylindrical cavities.
  • the wet tablets are pushed out using pins, which are accurately aligned to the cavities, and dried.
  • the method produces a porous, fragile, rapidly dissolving tablet.
  • a high degree of weight variation occurs and this attribute, coupled with inter-tablet migration of nitroglycerin, does not adequately preserve satisfactory content uniformity upon storage.
  • the higher content variation which occurs after aging of the tablets, even when stored in tightly closed glass containers, is attributed to inter-tablet migration.
  • this method has certain disadvantages; among them are the need to incorporate stabilizing agents like PVP, or the nitroglycerin itself, in alcohol and the subsequent removal of this solvent. It is preferable to employ nitroglycerin in a non-alcoholic solution for safety purposes. Also, wet granulations may require a binder which would retard and reduce the release (dissolution) of nitroglycerin from the tablet matrix. In addition, the extra handling and safety concerns with the processing of a wet granulation make the use of this technique less desirable.
  • an improved stabilized nitroglycerin tablet appears to be the use of a direct compression technology. By this means the complexity and safety concerns with the wet granulation process is obviated. Although much is known about the problem of nitroglycerin instability, an improved dry compression formulation which closely matches the original sublingual tablet has not been produced. Such a tablet would preferably meet the USP requirements for nitroglycerin molded tablets, be comparable to the molded tablets in texture, size and weight, and effectively reduce the potency loss and inter-tablet migration of the drug.
  • the literature reports a number of stabilized compositions, but none have been prepared by direct compression technology to mimic the properties of a molded tablet.
  • the lack of technical improvement relates to the complexity of the formulation with respect to selection of excipients and stabilizing agents which can be used to closely mimic the physical and chemical attributes of molded tablets and afford a significantly improved stability, and similar disintegration and bioavailability.
  • compositions such as tablets, containing nitroglycerin comprised of: nitroglycerin, glyceryl monostearate, calcium stearate, silica, starch and lactose are stabilized against the migration of the active agent from tablet to tablet when such tablets are in contact with each other.
  • the compositions are of the same taste and similar mouth feel as molded compositions which have been available heretofore.
  • the nitroglycerin containing tablets exceed the USP specifications and are bioequivalent to molded tablets.
  • compositions can be prepared by a direct compression method.
  • direct compression technology provides compositions which can be readily produced in an inexpensive, facile, efficient, hazard free and environmentally safe manner.
  • nitroglycerin, glyceryl monostearate, hydrous lactose, calcium stearate, pregelatinized starch and hydrophobic fumed silica are blended and then compressed to form the sublingual tablet.
  • the active agent of the present invention is nitroglycerin.
  • the novel pharmaceutical compositions of this invention can contain from about 0.5 to about 2 weight % of nitroglycerin, said weight % based on the total composition weight. This permits a variety of dosage strengths to be manufactured.
  • nitroglycerin has a vapor pressure of about 0.00026 mm at 20°C and is a violent explosive which must be handled with great care.
  • Commercially available nitroglycerin is, therefore, diluted to a concentration of 10 weight %, prior to the undertaking of pharmaceutical compounding and processing. This concentration of nitroglycerin was previously considered as flammable, but new Department of Transportation regulations have reclassified nitroglycerin concentrations above 2% as explosive. For safety reasons, nitroglycerin is diluted to a concentration below 2 weight %.
  • nitroglycerin dilution at a range that is suitable to produce various strength tablets that are currently prescribed.
  • One common dilution of a given percentage of nitroglycerin is readily compounded with additional excipients to produce the various strength tablets. While the strengths can be readily compounded using a 10% dilution, because of current regulations, compounding is performed, and exemplified herein, using a lower 1.95% dilution.
  • the diluent is comprised of the main ingredient, lactose.
  • Lactose influences, to a great extent, the flow behavior, compressibility and the taste of the compositions. It has been discovered that the presence of greater than about 90%, preferably about 95 to about 98%, weight % of lactose, said weight % based on the diluent weight, is surprisingly advantageous. In terms of weight % based on total tablet weight, preferably about 85 to about 95, optimally about 88 to about 93, weight % of lactose is present.
  • lactoses there are many lactoses known to those skilled in the art that are included in the scope of the present invention. As an example which is not meant to limit the scope of the invention, there are a number of well known commercially available lactoses in the market such as anhydrous lactose and hydrated lactose forms - monohydrates (TABLETTOSE sold by Meggle Co. of Germany), hydrous lactose fine, hydrous lactose fast flow and hydrous lactose G-200. Different grades of hydrous or anhydrous lactose may be used that enable the preparation of tablets with good compressibility, low friability and quick disintegration as well as affording protection from flammability.
  • anhydrous lactose and hydrated lactose forms - monohydrates TABLETTOSE sold by Meggle Co. of Germany
  • hydrous lactose fine hydrous lactose fast flow
  • hydrous lactose G-200 Different grades of hydrous or anhydrous lactose may be used that enable the preparation of tablets
  • additional excipients are included in the diluent along with the lactose.
  • One of these additional excipients is an anti-sticking agent.
  • silicas there are a number of silicas known to those skilled in the art, and the present invention is meant to broadly encompass all of these silicas.
  • the silicas can be precipitated (SYLOID® sold by Davison Division, W. R. Grace Company) or fumed, amorphous, colloidal or crystalline and in an anhydrous or hydrous form.
  • Fumed silica or silicon dioxide (SiO 2 ) is a colorless, tasteless amorphous powder that is insoluble in water and acids.
  • These colloidal silica particles are sintered together in chain-like formations that possess surface areas of 50 to 400 M 2 /g, depending upon the grade.
  • Hydrophobic fumed silicas are well known commercially available materials, e.g. AER-O-SIL® R-972 sold by Degussa, Inc. of Teterboro, N.J., CAB-O-SIL® N70-TS sold by Cabot Corp. of Tuscola, Ill., TULLANOX® 500 sold by Tulco, Inc., (all of which are preferred for use herein), of the general class of amorphous precipitated silicas but of the pyrogenic (fumed) type which provide, according to Kirk-Othmer's Encyclopedia of Chemical Technology (Third Edition) Vol. 20 at pages 768 and 778-779, an ultimate particle size of 1-100 nm, and an aggregate particle size of 2-3 ⁇ m. Hydrophobic silicas are discussed in Kirk-Othmer's Encyclopedia of Chemical Technology (Third Edition) Vol. 7 at pages 440-441.
  • compositions of the present invention also include the presence of starch.
  • starch There are many different starches known to those of skill in the art and the present invention includes, but is not limited to those listed in Grant &hackh's Chemical Dictionary, Fifth Edition.
  • a preferred starch of the present invention is pregelatinized starch.
  • the starch is present in an amount from about 5 to about 15 weight %, preferably about 5 to about 10 weight %, based on the total tablet weight.
  • nitroglycerin is a volatile compound that exhibits poor physical stability when formulated without a stabilizer.
  • the presence of the stabilizer decreases the potency loss of nitroglycerin in tablets, and thus its addition is important.
  • the preferred stabilizer of the present invention is glyceryl monostearate.
  • Glyceryl monostearate is a waxy material that decreases the disintegration time of nitroglycerin tablets.
  • a disintegrant is preferably employed in the present invention. It is widely known to those of skill in the pharmaceutical development area what constitutes a disintegrant and the amounts to be employed in pharmaceutical compositions.
  • Non-limiting examples of common disintegrants include one or more water dispersible cellulose derivatives such as microcrystalline cellulose, sodium croscarmellose, starch, and starch derivatives such as sodium carboxymethylstarch.
  • the diluted nitroglycerin is blended with a preblend of the stabilizer (i.e., glyceryl monostearate) and diluent (i.e., lactose). Then the anti-sticking agent (i.e., silica), more diluent and the disintegrant are added to the blend.
  • the stabilizer i.e., glyceryl monostearate
  • diluent i.e., lactose
  • the conventional procedure for making compacts requires the addition of a lubricant to the mixture before compression. Compression is accomplished by subjection of the dry blend under pressures by moveable punches operating in a die wherein the blend is confined.
  • the lubricants are necessary to allow the ready ejection of the formed compact and to prevent the binding of the punches in the die. Lubrication is required only at the tablet-die interface to prevent sticking of the newly formed compact to the die walls.
  • existing practical approaches to tablet lubrication require homogeneous distribution of lubricant within the entire tablet formulation.
  • a hydrophobic lubricant is preferred. Even more preferred is a lubricant which is the alkali metal salt of a fatty acid.
  • calcium stearate is the lubricant of choice in the present invention (calcium stearate is a well known commercially available material, e.g. calcium stearate NF powder sold by Mallinckrodt of St. Louis, MO).
  • Another aspect of this invention relates to the process for preparing the novel stabilized nitroglycerin tablets having the compositions described hereinbefore.
  • the process by which the stabilized nitroglycerin tablets are prepared comprises the steps of: (a) commingling nitroglycerin with lactose to produce a nitroglycerin dilution (current regulations require that the content of the active agent be about 2 percent); (b) adding and mixing the nitroglycerin dilution with an excipient or combination of excipients selected from the group described hereinbefore to produce a blend; (c) compressing the blend under a force of about 200 to about 800 kg; and (d) thereafter, recovering the blend as a compressed product having a hardness of about 1-4 kp.
  • One embodiment of the present invention provides for the preparation of the formulation by milling glyceryl monostearate along with a small portion of hydrous lactose.
  • hydrophobic fumed silica is milled along with a small portion of hydrous lactose.
  • Diluted nitroglycerin is blended with the milled glyceryl monostearate/hydrous lactose mixture in a blender for 5 minutes.
  • an intensifier-bar is turned during mixing.
  • the milled hydrophobic fumed silica/hydrous lactose mixture an a disintegrant, such as pregelatinized starch are added and blended for about 5 minutes.
  • a lubricant such as calcium stearate, is then added.
  • Blending for the purposes of discovering the present invention has been accomplished through the use of a V-blender. It should be understood, however, that there are different blending techniques known by those skill in the art that may be used with similar results. Variations of all blending times discussed herein of ⁇ 50% are permitted to obtain blend uniformity.
  • compositions of the present invention are tablets. Therefore, conventional tableting equipment and standard tableting procedures are applied to the blended mixture to prepare compacted sublingual nitroglycerin tablets having improved stability. Compression is accomplished by subjecting the blended mix to high pressures by moveable punches operating in a die wherein the tablet mix is confined.
  • the thoroughly blended mixture is directly compressed into tablets on a tablet machine. While any tablet machine known to those skilled in the art may be used to compress the blended mixture into tablet, in a preferred embodiment, tablets are compressed on any rotary press with weight control at a force of about 200 to about 800 kg at an average speed of about 75 RPM (65-85 RPM). Most preferably, an instrumented tablet press is employed for better control of tablet weights.
  • the tablets are packaged and/or stored for a period of time. Tablets can be packaged in glass amber vials (25-100 tablets per vial).
  • the compacted pharmaceutical tablets of the present invention it is a desirable characteristic of the compacted pharmaceutical tablets of the present invention to be bioequivalent to molded nitroglycerin tablets.
  • the bioavailability of the active ingredient is not impeded by the processing or the excipients added to make a stable compressed nitroglycerin sublingual tablet
  • the present invention is surprisingly advantageous by including excipients which are necessary to impart physical characteristics essential for manufacture with existing compaction equipment, but without having adverse effects on the availability of nitroglycerin.
  • the initial disintegration time of the compositions of the present invention is about 25 seconds.
  • the disintegration of the compositions of the present invention is on the order of about 10 to about 40 seconds.
  • the disintegration of the compositions of the present invention is on the order of about 20 to about 30 seconds.
  • a free flowing granulation is crucial in quickly and evenly filling the die cavity during compression in a high speed press. Uneven or poor flow of granulation results in erratic filling of the die cavity and consequently, weight variation. Small differences in weight are magnified as large relative standard deviations for a tablet with an average weight as low as 35 mg. Because diluted nitroglycerin is a non-flowable, wet appearing mixture, it is a major contributor to flow problems in a powder blend. Without the aid of the excipients, the impedance to flow of granulation is expected to be seen at the highest strength (0.6 mg) where the greatest amount of nitroglycerin is incorporated into the blend.
  • the compressed nitroglycerin compositions of the present invention show less weight variation than previously known molded nitroglycerin compositions.
  • the weight variations of the compositions of the present invention are less than about 3% RSD.
  • the weight variations of the compositions of the present invention are on the order of 1-2% RSD.
  • the weight variations of the compositions of the present invention are about 1% RSD.
  • the compressed nitroglycerin compositions of the present invention also show better content uniformity than previously known molded nitroglycerin compositions.
  • the content uniformity variations of the compositions of the present invention are less than about 4% RSD.
  • the content variations of the compositions of the present invention are on the order of about 1% RSD to about 3% RSD.
  • the content variations of the compositions of the present invention are on the order of about 2% RSD.
  • the compressed nitroglycerin compositions of the present invention show significantly less friability than previously known molded nitroglycerin compositions, thus indicating improved structural integrity against external mechanical forces, e.g. during packaging, shipping, handling.
  • the friability of the compositions of the present invention is less than about 1%.
  • the friability of the compositions of the present invention is less than about 0.5%.
  • the compressed nitroglycerin compositions of the present invention show consistent thickness and hardness when compressed into tablets.
  • the thickness of tablets compressed from the compositions of the present invention is 0.07 x 25.4 mm - 0.10 x 25.4 mm (about 0.07 to about 0.10").
  • the hardness of tablets compressed from the compositions of the present invention is greater than about 1 kp.
  • the hardness of tablets compressed from the compositions of the present invention is on the order of about 1-4 kp.
  • the tablet hardness is sufficient to enable handling without risk of tablet breakage.
  • the compressed sublingual tablets of the present invention may be multilayer tablets and have various shapes, colors, and sizes. Further, it will be apparent that these tablets once formed may be coded and/or coated by a variety of procedures well-known to those skilled in the art. Still further, the coated tablets may be subjected to a polishing procedure or other routine processes, which have been carried out on compressed tablets prior to this invention.
  • tablette as used herein includes tablets of any shape and includes caplets, which are tablets having a capsule shape. If desired, a pharmaceutically acceptable coloring agent may be added to the tablets.
  • the compressed tablets may also be coated with a pharmaceutically acceptable polymer, gelatin, or sugar coating. The addition of coloring agent, polymer, gelatin, or sugar coating can be accomplished by anyone skilled in the art.
  • the present invention also comprises a product prepared by the methods of manufacturing the compressed nitroglycerin-containing compositions described above.
  • the product is preferably a compressed nitroglycerin sublingual tablet prepared according to a process having the steps comprising: (a) blending ingredients selected from the group consisting of nitroglycerin, hydrous lactose, glyceryl monostearate, calcium stearate, starch and hydrophobic fumed silica; (b) compressing said blend under a pressure of 200 to about 800 kg; and (c) recovering said blend as a compressed product.
  • the process further comprises the step of diluting the nitroglycerin prior to blending the ingredients.
  • the preferred ingredients in the process are nitroglycerin, lactose monohydrate, calcium stearate, silica, starch and glyceryl monostearate in the following amounts: 0.5 to about 5 weight % of nitroglycerin; 88 to about 93 weight % of lactose; 0.3 to about 0.5 weight % of silica; 0.3 to about 0.5 weight % of calcium stearate; 5 to about 15 weight % of starch and about 0.5 to about 10 weight % of glyceryl monostearate.
  • the products, preferably compressed into tablets, and made by the process have the following physical properties: disintegration on the order of about 20 to about 30 seconds; weight variations on the order of about 1 to about 2% RSD; content variations on the order of less than about 4% RSD; friability on the order of less than about 1%; thickness on the order of 0.07 x 25.4 mm - 0.10 x 25.4 mm (about 0.07" - 0.10"), and hardness on the order of about 1-4 kp.
  • the amount of Nitroglycerin USP weighed was calculated based on assay results.
  • the total amount of Lactose Monohydrate needed was adjusted based on the amount of Nitroglycerin used.
  • Glyceryl Monostearate, NF Myvaplex 600P
  • Lactose Monohydrate NF were milled together and collected in a drum. Silicon Dioxide and Lactose Monohydrate were milled together and collected in another drum. Diluted Nitroglycerin USP and the milled Glyceryl Monostearate/Lactose Monohydrate mix were loaded into a blender equipped with an intensifier bar. The ingredients were blended for ten minutes with the intensifier bar ON. Then, the milled Silicon Dioxide/Lactose Monohydrate mix and the Pregelatinized Starch were added to the PK blender and blended for five minutes with the intensifier bar ON. Calcium Stearate was added to the blender and the materials were blended for five minutes. The powder blends were compressed into tablets using suitable tablet press machine.
  • lactose was used as the diluent, pregelatinized starch as the disintegrant, glyceryl monostearate as the stabilizer, silicon dioxide as the flow-aid agent and calcium stearate as the lubricant.
  • Example 1 Example 2 Stability Cond.
  • Tablet samples were tested for nitroglycerin content uniformity (CU) initially and after twelve months of storage at 25°C/60% RH. The results show low variability (RSD ⁇ 2 %) and the USP specification of 75.0 - 135.0% of Label Claim was met. Tablet No.
  • Example 1 Example 2 Initial (Bulk) 12 Months Initial (Bulk) 12 Months 25's 100's 25's 100's 1 100.3 99.0 98.7 104.3 100.5 98.6 2 100.3 98.4 97.1 101.6 99.6 99.7 3 97.8 99.9 97.8 101.5 102.6 100.5 4 101.6 98.9 99.3 104.2 100.5 98.9 5 99.8 100.7 99.6 100.9 100.7 100.6 6 100.3 99.7 100.7 103.2 99.3 105.1 7 101.0 100.6 98.5 102.4 100.3 100.5 8 96.3 100.0 97.4 100.6 100.2 99.8 9 97.4 97.9 96.1 103.3 102.0 98.9 10 99.1 97.8 97.5 101.5 100.7 98.9 Average: 99.4 99.3 98.3 102.4 100.6 100.2 %RSD: 1.7 1.1 1.4 1.3 1.0 1.9
  • the following table shows the 12-month chemical stability results (assay and degradation products) for the two examples stored in bottles of 25's and 100's at 25°C/60%RH and 40°C/75%RH conditions. All results met the USP assay specification of 90.0 - 115.0% LC and no significant change in degradation products was observed.

Claims (19)

  1. Stabile Zusammensetzung, umfassend wirksame Mengen von Nitroglycerin, Lactose, Kieselerde, Stärke, Glycerinmonostearat und Schmiermittel, wobei Nitroglycerin das einzige pharmakologische Wirkmittel ist.
  2. Zusammensetzung nach Anspruch 1, bei welcher die Zusammensetzung als Sublingualtablette zur Verfügung steht.
  3. Zusammensetzung nach Anspruch 1, bei welcher die Stärke vorgelatiniserte Stärke ist, die als Desintegrationsmittel verwendet wird.
  4. Zusammensetzung nach Anspruch 1, bei welcher die Kieselerde Kieselpuder ist.
  5. Zusammensetzung nach Anspruch 1, bei welcher das Schmiermittel ein Alkalimetallsalz ist.
  6. Zusammensetzung nach Anspruch 1, bei welcher die Lactose wasserhaltige Lactose ist.
  7. Zusammensetzung nach Anspruch 1, bei welcher das Stabilisiermittel Glycerinmonostearat in einer Menge von etwa 0,5 bis etwa 10 Gew.-% ist.
  8. Zusammensetzung nach Anspruch 1, welche die folgenden Mengen umfasst: 0,5 bis etwa 5 Gew.-% Nitroglycerin; mehr als etwa 90 Füllstoff-Gew.-% Lactose; 0,1 bis etwa 1 Gew.-% Kieselerde; 0,1 bis etwa 1 Gew.-% Calciumstearat; 5 bis etwa 15 Gew.-% Stärke; und etwa 0,5 bis etwa 10 Gew.-% Glycerinmonostearat.
  9. Zusammensetzung nach Anspruch 1, bei welcher sich die Zusammensetzung in der Grössenordnung von etwa 20 bis etwa 30 Sekunden desintegriert.
  10. Zusammensetzung nach Anspruch 1, bei welcher die Gewichtsvariation der Zusammensetzung etwa 1 bis etwa 2 % des Variationskoeffizienten beträgt.
  11. Zusammensetzung nach Anspruch 1, bei welcher die Zusammensetzung folgende Eigenschaften aufweist: Desintegration in der Grössenordnung von etwa 20 bis etwa 30 Sekunden; Gewichtsvariationen in der Grössenordnung von etwa 1 bis etwa 2 % des Variationskoeffizienten; Gehaltsvariationen in der Grössenordnung von weniger als etwa 4 % des Variationskoeffizienten; Bröckeligkeit in der Grössenordnung von weniger als etwa 1 %; Dicke in der Grössenordnung von 0,07x25,4 mm - 0,10x25,4 mm (etwa 0,07" - 0,10"); und Härte in der Grössenordnung von etwa 1 - 4 kp.
  12. Zusammensetzung nach Anspruch 1, bei welcher die Zusammensetzung eine komprimierte Tablette ist.
  13. Stabile komprimierte Tablette, im wesentlichen bestehend aus wirksamen Mengen von Nitroglycerin, Lactose, Kieselerde, vorgelatiniserter Stärke, Glycerinmonostearat und Schmiermittel, wobei Nitroglycerin das einzige pharmakologische Wirkmittel ist.
  14. Zusammensetzung nach Anspruch 13, bei welcher die Kieselerde Kieselpuder ist.
  15. Zusammensetzung nach Anspruch 14, bei welcher das Schmiermittel Calciumstearat ist.
  16. Zusammensetzung nach Anspruch 15, bei welcher die Lactose wasserhaltige Lactose ist.
  17. Trockenes, komprimiertes, Nitroglycerin enthaltendes Produkt, hergestellt durch die Verfahrensschritte, welche umfassen: (a) Kombinieren von Nitroglycerin mit Lactose zur Produktion einer Nitroglycerinverdünnung, in welcher der Gehalt an Wirkmittel etwa 2 Prozent oder weniger beträgt; (b) Zugeben und Mischen der Nitroglycerinverdünnung mit Kieselerde, Schmiermittel, Glycerinmonostearat, Stärke und gegebenenfalls zusätzlicher Lactose zur Produktion eines Gemisches; (c) Komprimieren des Gemisches; und (d) danach, Gewinnen der Gemisches als komprimiertes Produkt.
  18. Produkt nach Anspruch 17, bei welchem die Stärke vorgelatiniserte Stärke ist.
  19. Verfahren zur Herstellung eines trockenen, komprimierten, Nitroglycerin enthaltenden Produkts, das hergestellt ist durch die Verfahrensschritte, welche umfassen: (a) Kombinieren von Nitroglycerin mit Lactose zur Produktion einer Nitroglycerinverdünnung, in welcher der Gehalt an Wirkmittel etwa 2 Prozent oder weniger beträgt; (b) Zugeben und Mischen der Nitroglycerinverdünnung mit Kieselerde, Schmiermittel, Glycerinmonostearat, Stärke und gegebenenfalls zusätzlicher Lactose zur Produktion eines Gemisches; (c) Komprimieren des Gemisches; und (d) danach, Gewinnen der Gemisches als komprimiertes Produkt.
EP98948293A 1997-10-03 1998-09-16 Gepresste nitroglycerintablette und verfahren zu ihrer herstellung Expired - Lifetime EP1019039B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9830076T SI1019039T1 (en) 1997-10-03 1998-09-16 Compressed nitroglycerin tablet and its method of manufacture

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US6110597P 1997-10-03 1997-10-03
US61105P 1997-10-03
PCT/US1998/019356 WO1999017766A1 (en) 1997-10-03 1998-09-16 Compressed nitroglycerin tablet and its method of manufacture

Publications (2)

Publication Number Publication Date
EP1019039A1 EP1019039A1 (de) 2000-07-19
EP1019039B1 true EP1019039B1 (de) 2001-12-05

Family

ID=22033623

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98948293A Expired - Lifetime EP1019039B1 (de) 1997-10-03 1998-09-16 Gepresste nitroglycerintablette und verfahren zu ihrer herstellung

Country Status (16)

Country Link
US (1) US6500456B1 (de)
EP (1) EP1019039B1 (de)
JP (1) JP2001518500A (de)
KR (1) KR100569763B1 (de)
AT (1) ATE209911T1 (de)
AU (1) AU759018B2 (de)
BR (1) BR9812605B1 (de)
CA (1) CA2299231C (de)
DE (1) DE69802832T2 (de)
DK (1) DK1019039T3 (de)
ES (1) ES2169558T3 (de)
IL (1) IL134395A (de)
NZ (1) NZ502878A (de)
PT (1) PT1019039E (de)
TW (1) TWI228989B (de)
WO (1) WO1999017766A1 (de)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1323400A (en) * 1998-10-27 2000-05-15 Fuisz Technologies Ltd. Microparticles containing peg and/or peg glyceryl esters
US7815937B2 (en) * 1998-10-27 2010-10-19 Biovail Laboratories International Srl Quick dissolve compositions and tablets based thereon
US7815936B2 (en) 2001-10-30 2010-10-19 Evonik Degussa Gmbh Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions
US20040109889A1 (en) 2002-12-04 2004-06-10 Bunick Frank J. Surface treatment composition for soft substrates
US9358296B2 (en) 2003-02-24 2016-06-07 Pharmaceutical Productions Inc. Transmucosal drug delivery system
US10172810B2 (en) 2003-02-24 2019-01-08 Pharmaceutical Productions, Inc. Transmucosal ketamine delivery composition
US9254294B2 (en) 2003-02-24 2016-02-09 Pharmaceutical Productions Inc. Transmucosal hormone delivery system
US9498454B2 (en) 2003-02-24 2016-11-22 Pharmaceutical Productions Inc. Transmucosal drug delivery system
EP2316418A3 (de) * 2003-02-24 2011-09-21 Pharmaceutical Productions Inc. Tansmukosales System zur Wirkstofffreisetzung
US20070059346A1 (en) * 2003-07-01 2007-03-15 Todd Maibach Film comprising therapeutic agents
US7999003B2 (en) * 2003-08-26 2011-08-16 Mannatech, Incorporated Antioxidant compositions and methods thereto
US20060134202A1 (en) * 2004-12-22 2006-06-22 Hack Jacob C Homeopathic sublingual dosage forms and methods thereof
US9066847B2 (en) 2007-01-05 2015-06-30 Aceirx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
US8357114B2 (en) 2006-01-06 2013-01-22 Acelrx Pharmaceuticals, Inc. Drug dispensing device with flexible push rod
US8865743B2 (en) 2006-01-06 2014-10-21 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US8252328B2 (en) * 2006-01-06 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8753308B2 (en) 2006-01-06 2014-06-17 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8202535B2 (en) 2006-01-06 2012-06-19 Acelrx Pharmaceuticals, Inc. Small-volume oral transmucosal dosage forms
US9289583B2 (en) 2006-01-06 2016-03-22 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8252329B2 (en) 2007-01-05 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8535714B2 (en) 2006-01-06 2013-09-17 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
WO2008098195A2 (en) * 2007-02-09 2008-08-14 Todd Maibach Film comprising nitroglycerin
US20090004254A1 (en) * 2007-06-19 2009-01-01 Todd Maibach Film comprising active drugs
DK2182902T3 (en) * 2007-08-07 2015-04-13 Acelrx Pharmaceuticals Inc Compositions comprising sufentanil and triazolam for procedure sedation and analgesia using oral transmucosal dosage forms
US8945592B2 (en) * 2008-11-21 2015-02-03 Acelrx Pharmaceuticals, Inc. Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
US20110091544A1 (en) * 2009-10-16 2011-04-21 Acelrx Pharmaceuticals, Inc. Compositions and Methods for Mild Sedation, Anxiolysis and Analgesia in the Procedural Setting
ES2582309T3 (es) 2010-08-03 2016-09-12 G. Pohl-Boskamp Gmbh & Co. Kg Uso de trinitrato de glicerilo para el tratamiento de edema traumático
CA2827716C (en) * 2011-02-25 2019-05-14 G. Pohl-Boskamp Gmbh & Co. Kg Stabilized granules containing glyceryl trinitrate
PL2668947T3 (pl) 2012-05-31 2017-06-30 G. Pohl-Boskamp Gmbh & Co. Kg Indukcja arteriogenezy donorem NO, takim jak nitrogliceryna
EP2668948A1 (de) * 2012-05-31 2013-12-04 G. Pohl-Boskamp GmbH & Co. KG Verwendung von stabilisierten Körnchen mit Glyceryltrinitrat für Arteriogenese
US9248099B2 (en) 2012-05-31 2016-02-02 Desmoid Aktiengesellschaft Use of stabilized granules containing glyceryl trinitrate for arteriogenesis
WO2014034860A1 (ja) * 2012-08-31 2014-03-06 アステラス製薬株式会社 経口投与用医薬組成物
KR102237799B1 (ko) 2012-11-14 2021-04-08 더블유.알. 그레이스 앤드 캄파니-콘. 생물학적 활성 물질 및 비-정렬된 무기 산화물을 함유하는 조성물
US20140303227A1 (en) * 2013-03-14 2014-10-09 Pharmaceutical Productions Inc. Transmucosal hormone delivery system
EP2878310B1 (de) 2013-11-29 2017-01-11 G. Pohl-Boskamp GmbH & Co. KG Sprühbare wässrige Zusammensetzung mit Nitroglycerin
CN105007904A (zh) * 2014-02-07 2015-10-28 科学实验室药物公司 全天然无毒舌下药物递送系统
CN113679682A (zh) * 2020-05-19 2021-11-23 珠海润都制药股份有限公司 一种硝酸甘油舌下片及其制备方法
CN114469881A (zh) * 2022-03-14 2022-05-13 河北坤安药业有限公司 一种硝酸甘油片及其制备方法
CN115154431B (zh) * 2022-07-21 2024-03-12 南京卓康医药科技有限公司 一种硝酸甘油片剂及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2357503A1 (de) * 1973-11-17 1975-05-28 Cassella Farbwerke Mainkur Ag Verfahren zur herstellung von festen carbocromen-hydrochlorid enthaltenden praeparaten
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
WO1996036330A2 (en) * 1995-05-17 1996-11-21 Cedars-Sinai Medical Center Compositions containing fatty acids for improving digestion and absorption in the small intestine
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use

Also Published As

Publication number Publication date
CA2299231A1 (en) 1999-04-15
DE69802832D1 (de) 2002-01-17
AU759018B2 (en) 2003-04-03
BR9812605B1 (pt) 2009-01-13
KR20010030839A (ko) 2001-04-16
DK1019039T3 (da) 2002-03-25
NZ502878A (en) 2002-03-01
ATE209911T1 (de) 2001-12-15
IL134395A0 (en) 2001-04-30
WO1999017766A1 (en) 1999-04-15
DE69802832T2 (de) 2002-06-20
ES2169558T3 (es) 2002-07-01
KR100569763B1 (ko) 2006-04-11
IL134395A (en) 2005-08-31
JP2001518500A (ja) 2001-10-16
AU9489398A (en) 1999-04-27
CA2299231C (en) 2003-03-18
EP1019039A1 (de) 2000-07-19
TWI228989B (en) 2005-03-11
US6500456B1 (en) 2002-12-31
BR9812605A (pt) 2000-08-01
PT1019039E (pt) 2002-04-29

Similar Documents

Publication Publication Date Title
EP1019039B1 (de) Gepresste nitroglycerintablette und verfahren zu ihrer herstellung
ES2940341T3 (es) Formulación y proceso de compresión directa
RU2338532C2 (ru) Диспергируемые таблетки деферасирокс
AU771705B2 (en) Glyburide composition
US8367106B2 (en) Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby
JP2005533045A (ja) 経口崩壊錠およびその製造法
US7494668B2 (en) Fast water-dispersible domperidone tablets
US10881610B2 (en) Orally disintegrating tablet
JPH04210919A (ja) ピモベンダン経口投与製剤
JP5775463B2 (ja) 溶出安定性製剤
WO2007077135A1 (en) Pharmaceutical composition containing montelukast
US20110257159A1 (en) Orally disintegrating tablet formulations of mirtazapine and process for preparing the same
US8906949B2 (en) Orally disintegrating tablets of zolmitriptan and process for preparing the same
EP2471520B1 (de) Pharmazeutische Levetiracetam-Zusammensetzungen
CZ20031899A3 (en) Pharmaceutical tablet comprising paroxetine mesylate
Comoglu et al. Formulation, in vitro and in vivo evaluation of taste masked rasagiline orally fast disintegrating tablets (ODTS)
EP1729735B1 (de) Verfahren zur herstellung von komprimierten festen dosierungsformen, das gut zur verwendung mit schlecht wasserlöslichen arzneistoffen geeignet ist, und danach hergestellte komprimierte feste dosierungsformen
MXPA00001517A (en) Compressed nitroglycerin tablet and its method of manufacture
SK53798A3 (en) Captopril tablets
EP4061328B1 (de) Orodispergierbare zonisamidtabletten
JP4573542B2 (ja) ビタミンｂ１誘導体組成物
EP1787642A1 (de) Herstellungsverfahren für komprimierte, feste Dosierungsformen, gut geeignet für Gebrauch bei Medikamenten mit niedriger Wasserlöslichkeit und dadurch hergestellte komprimierte, feste Dosierungsformen
JP2007246539A (ja) 速溶性医薬組成物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000503

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20000503;LT PAYMENT 20000503;LV PAYMENT 20000503;MK PAYMENT 20000503;RO PAYMENT 20000503;SI PAYMENT 20000503

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

17Q First examination report despatched

Effective date: 20001010

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20000503;LT PAYMENT 20000503;LV PAYMENT 20000503;MK PAYMENT 20000503;RO PAYMENT 20000503;SI PAYMENT 20000503

REF Corresponds to:

Ref document number: 209911

Country of ref document: AT

Date of ref document: 20011215

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 69802832

Country of ref document: DE

Date of ref document: 20020117

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SCHMAUDER & PARTNER AG PATENTANWALTSBUERO

ET Fr: translation filed
REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20020110

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20020400331

Country of ref document: GR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2169558

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: SI

Ref legal event code: IF

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20080627

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20080731

Year of fee payment: 11

Ref country code: ES

Payment date: 20080919

Year of fee payment: 11

Ref country code: DK

Payment date: 20080811

Year of fee payment: 11

Ref country code: CH

Payment date: 20080708

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20080813

Year of fee payment: 11

Ref country code: MC

Payment date: 20080811

Year of fee payment: 11

Ref country code: IT

Payment date: 20080915

Year of fee payment: 11

Ref country code: IE

Payment date: 20080718

Year of fee payment: 11

Ref country code: FR

Payment date: 20080904

Year of fee payment: 11

Ref country code: FI

Payment date: 20080903

Year of fee payment: 11

Ref country code: AT

Payment date: 20080811

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20080808

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20080930

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20080905

Year of fee payment: 11

Ref country code: BE

Payment date: 20080925

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20080910

Year of fee payment: 11

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20080704

Year of fee payment: 11

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: SCHMAUDER & PARTNER AG PATENT- UND MARKENANWAELTE VSP;ZWAENGIWEG 7;8038 ZUERICH (CH)

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20100316

BERE Be: lapsed

Owner name: *WARNER-LAMBERT CY

Effective date: 20090930

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20100401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100316

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20090916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20100531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20100528

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100401

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100406

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090917

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20110718

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110706

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090917